Table 2.

The immune mechanism related to tumor metastasis.

Immune Checkpoint	Tumor-Metastasis-Related Immune Response
Immune inhibitors
PD-1 and PDL-1/2	① inhibit proximal T cell receptor and CD28 ② attenuate activated T cells co-stimulation ③ inhibit the activation of peripheral activated T cells ④ PTEN can boost the above three ⑤ Akt can promote the expression of PDL-1
CTLA-4	inhibits self-reactive T cells by binding with B7 to competitive inhibit CD28 co-stimulation
LAG-3	① competitively binds with MHC-II ② negative regulation for T cell expansion with boosting T cell exhaustion ③ activates DCs
TIGIT and CD155	① has a synergistic effect to interact with CD155(TIGIT ligand) and inhibit T cells and NK cells ② TIGIT binds with CD155 and competitively inhibits DNAM-1 ③ ITIM (a negative signal transduction pathway CD155 binds with CD96) can inhibit the activation of NK cells
TIM-3	① inhibits type-I immunity and peripheral immune tolerance ② inhibits the components of TCR signals, stops the activation of T cells, and boosts the exhaustion of CD8+ T cell ③ TIM-3 can work with PD-1
SIGLEC-15	① delivers a negative signal by binding with a presumptive receptor on T cells and suppresses the activation of antigen-specific T cells ② restores the role of antitumor immunity in TME ③ hS15-hIg and mS15-mIg can be used to inhibit T cell activation ④ SIGLEC-15 can work with PD-1
IDO-1	① The deletion of Trp makes tRNA of T cells out of control ② Activating the signal transduction pathways of GCN2 and mTOR makes T cell anergic signals ③ The expression of Kyn is related with T cells necrosis, rendering  CD4+ T cells into Tregs ④ IDO-1 can work with PD-1
VISTA (B7-H5)	① inhibits CD4+ T cells by binding with its ligand VIG-3 ② increases the threshold of T cells activation via inhibiting TCR signals ③ VISTA can work with PD-1
VTCN1 (B7-H4)	① inhibits the proliferation of CD4+T cells and its differentiation toward Th1, Th17 cells ② makes the transient increase of Tregs ③ inhibits the secretion of cytokines
CD276 (B7-H3)	① inhibits the proliferation and activation of T cells and the secretion of some cytokines like IFN-γ and TNF-α ② The decreased expression of CD276 will lead to the tumor-metastasis-related protein MMP-2, STAT3, IL-8 get reduced signals ③ CD276 can work with PD-1 and CTLA-4
CD70	① renders the TME into the suppressive environment, the activation of NK cells will be inhibited, the expression of MHC protein can be reduced, T cells can be anergic ② activates Tregs and lead to the apoptosis of lymphocytes, as well as inhibits T cells inflammatory response, especially for CD4+T cells signals ③ CD70 works via CASPASE, JNK and NIK/IKK signal pathways to interact with CD27
CD47	① CD47 works via SIRPα to inhibit the phagocytosis of macrophages ② Represses innate and adaptive immune ③ Helps tumor cells to escape from immune surveillance
Immune activators
TNFSF14 (LIGHT)	① regulates T cells co-stimulation via binding with HVEM and LTBR and boost the infiltration of CD8+T cells into tumors ② normalizes the tumor vessels ③ makes some cytokines increased, such as IFN-γ, TNF-α, MIG
TNFRSF4	TNFRSF4 mainly promotes the capacity of T cells ① activates T cells and memory T cells ② boosts the proliferation of CD4+ and CD8+ T cells, to accelerate CD4+ T cells to differentiate into Th1 and Th2 cells via NK-κB and NFAT signal transduction pathways
TNFRSF9	① accelerates the activation and proliferation of CD4+ and CD8+ T cells ② accelerates the cytotoxic effect of TCR and CD8+ T cells ③ accelerates the differentiation of effector memory CD8+ T cells ④ enhances the APCC cytotoxic effect of NK cells
TNFRSF18 (GITR)	① regulates the role of co-stimulatory molecules in the activation process of effector T cells ② restores the function of tumor infiltration lymphocytes
CD28	① provides the second messenger for TCR to facilitate T cells activation ② promotes the function of effector T cells and Tregs ③ CD28 can work with PD-1 and CTLA-4